CRISPR to the rescue!

The Boston Globe has an article announcing the imminent approval of Casgevy, a CRISPR-based treatment for sickle cell disease that has already been approved in Britain.

It is hard to overstate how transformative CRISPR has been for genetics research, and how promising it is for gene therapy. Sickle cell disease was always the low-hanging fruit, but there are plenty of other conditions that are being targeted for CRISPR therapy.

To explain how Casgevy works, it’s first important to understand what sickle cell disease is:

Sickle cell disease is caused by a specific mutation in the human beta globin protein, part of the hemoglobin protein that carries oxygen in our blood. It persons who carry the sickle cell mutation in both beta globin gene copies, their hemoglobin tends to polymerize at low oxygen tension, causing their red blood cells to adopt an abnormal “sickle” shape. This results in (a) the red blood cells getting trapped in capillaries, causing painful infarcts and gradual organ destruction and (b) damage to and loss of the red blood cells resulting in anemia.

So how does Casgevy fix this problem? Not by repairing the sickle cell mutation. Instead, Casgevy therapy rests on decades of research on human globin molecular, cellular and developmental biology. A short tutorial on beta globin developmental biology:

Our hemoglobin molecules each contain two alpha globin proteins and two beta globin proteins. While the same alpha globin genes are expressed throughout life, different beta globin genes are expressed at different stages: there are embryonic beta globin genes that are only expressed transiently as the blood islands form in embryos. These are then switched off and the fetal beta globin genes are expressed throughout the balance of gestation. Right before birth, the fetal beta globin genes are switched off, and the “adult” beta globin gene is expressed for the rest of life. It is this “adult” beta globin gene that is mutant in sickle cell disease patients.

What Casgevy does is inactivate a gene, BCL11A, that normally shuts off the fetal hemoglobin genes during post-partum life. Without BCL11A, fetal beta globin—which doesn’t cause sickling—can be expressed and competes with the sickle cell beta globin for the alpha globin and hemoglobin formation. If fetal beta globin expression exceeds ca. 20% of the total beta globin expression, patients can experience at least some relief from painful infarcts and anemia.

It is important to note that this gene surgery takes place in the patient’s hematopoietic stem cells. Once the edited stem cells are returned to the patient, they will continue to make the therapeutic red blood cells for the rest of the person’s life.

Gene editing for sickle cell disease